Tyrosine-specific protein kinases (PTK's) were first detected in studies of transforming retroviruses. Several of these retrovirally-encoded oncogenes were derived from cellular genes whose products are now known to be intracellular tyrosine kinases thought to act as signaling molecules. Studies of oncogenic intracellular PTK's have demonstrated that if the regulatory restraints are removed by mutation or deletion of key sequences, malignant transformation may ensue (J. Bishop, Leukemia, 2: 199-208, 1988). Multiple receptor tyrosine kinases have also been identified; many play a critical role in the transmembrane transfer of growth and differentiation signals. These receptors are normally activated by soluble or membrane-bound ligand (A. Ullrich & J. Schlessinger, Cell, 61: 203-12, 1990). However, several transforming oncogenes derived from receptor tyrosine kinases have demonstrated that these too can be mutated so as to escape normal control mechanisms. For example, the transforming ability of the c-fms and neu proto-oncogenes can be induced by a single amino acid change in the extracellular or transmembrane domain (M. Roussel et al., Cell, 55: 979-88, 1988; J. Woolford et al., Cell, 55: 965-77, 1988; H. Maguire & M. Greene, Semin Oncol, 16: 148-55, 1989). Additionally, retroviral transduction has created viral oncogenes such as v-erbB, v-kit, and v-sea by a more drastic loss of sequence (H. Kung et al., Dev Biol Stand, 72: 139-144, 1990; P. Besmer et al., Nature, 320: 415-21, 1986; J. Knight et al., Genes Dev, 2: 247-58, 1988). In these cases, a large deletion of the extracellular domain abrogates ligand dependence, resulting in constitutive tyrosine kinase activity.
Another example of extracellular domain deletion during viral transduction was the recently described chicken RPL30 virus which contained a truncated tyrosine kinase, v-ryk (R. Jia et al., J Virol, 66: 5975-87, 1992). The corresponding proto-oncogene was postulated to encode a receptor type tyrosine kinase because the catalytic domain sequence resembled that of other receptor tyrosine kinases, but sequence of the extracellular region was unknown.